Lecture 13 Echinocandins and Terbinafine Flashcards
Give 3 examples of echinocandins
Caspofungin (oldest)
Micafungin
Anidulafungin (newest)
What is the mode of action of echinocandins?
bind to the Fks1p subunit = blocks B1,3-D-glucan synthesis
In what form are echinocandins given and why?
IV
Due to being a large molecule
Which species do echinocandins work on?
candida
Aspergillus
What is the licensed indication for caspofungin?
Invasive candidosis in adults
Aspergillosis as a refractory treatment i.e. must have tried another drug 1st
Empirical therapy for presumed fungal infection e.g. neutropenia, fever
What is the licensed indication for anidulafungin?
invasive candida in adults
What is the licensed indication for micafungin?
Invasive candidosis in children and adults
Oesophageal candidosis in adults
Prophylaxis against candidosis in adults or children e.g. for hematological diseases, bone marrow transplant, etc.
Explain the licensing trial for caspofungin comparing caspofungin and amphotericin B
Compared caspofungin and amphotericin B in nonneutropenic patients with candidaemia
No significant difference between drugs in successful outcomes
Significantly less renal toxicity and hypokalaemia in amphotericin B patients
Explain the licensing trial for caspofungin in use for refractory invasive aspergillosis
83 patients Favorable outcome: 37 Stable disease: 6 Failure of therapy: 40 Only 1 serious adverse event
Due to lack of comparison drug and small study size, 2nd line license given for this use
Explain the licensing trial for anidulafungin
Comparison between anidulafungin and fluconazole (standard treatment for candidosis at the time) in nonneutropenic patients with invasive candidosis
No of patients: 235
Successful outcomes significantly higher for anidulafungin
Number of adverse events about the same
Explain the licensing trial for micafungin
Compared micafungin and ambisome in patients with invasive candidosis
494 patients - half on each drug
The successful outcome of both drugs was similar
Less adverse effects with micafungin
Where are the majority of micafungin metabolized?
Caspofungin: >90% in blood and tissues
Anidulafungin: >90% in blood
Micafungin: hepatic metabolism
What are the toxicity risks associated with caspofungin?
Loss of potassium Fever Chills Mildly deranged liver functions Generally well tolerated
What are the toxicity risks associated with anidulafungin?
headache
nausea
mildly deranged liver functions
Generally well tolerated
What are the toxicity risks associated with micafungin?
Mildly deranged liver function
Headache
Generally well tolerated
What drugs does caspofungin interact with?
some immunosuppressants
steroids - in children
some antivirals and antibiotic
What drugs does anidulafungin interact with?
no known drug interactions
What drugs does micafungin interact with?
some immunosuppressants
Which species are and are not resistant to echinocandins and how?
resistance is rare
Candida albicans - resistance associated with mutations in the gene FSK1 gene of B 1-3 glucan synthase complex, particularly codon 645 Ser
C. glabrata - mutations in FSK1 and 2 genes associated with echinocandins resistance
Cryptococcus spp not susceptible - may be due to glucan synthase target alteration, efflux pumps or degradation pathways present
Explain the paradoxical effect with echinocandins and how this occurs
Initially, as the dose increases the growth of C. albicans decreases - very large doses sees an increase in growth
The effect is strain specific and dependent on growth medium - Also seen in Aspergillus fumigatus
Possible mechanism theories:
Upregulation of chitin biosynthesis to counteract the reduced glucan production
Upregulation of cell wall integrity pathway (protein kinase C)
Name the one drug in the allylamine class
Terbinafine
What is the mode of action of terbinafine?
Inhibition of squalene epoxidase - function is to catalyze a step in the ergosterol synthetic pathway
What form does terbinafine come in?
Tablets
gel
cream
spray
What is terbinafine indicated for?
Dermatophyte infections of the skin and nail
Cream for skin infections due to yeast
